Role of CCR1 in Cytokine Storm & Immunopathology after influenza infection

CCR1 在细胞因子风暴中的作用

• 批准号: 8424897
• 负责人: Troy D Randall
• 金额: $ 18.31万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-29 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424897
• 关键词: Acute; Antiviral Agents; Attenuated; Bacterial Infections; Birds; Brain; CCR1 gene; CX3CL1 gene; Cells; Cessation of life; Child; Data; Dose; Edema; Emerging Communicable Diseases; Encephalopathies; Epithelial; Exhibits; Hematopoietic; Hong Kong; Hypoxemia; Immune; Immunity; Infection; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Lead; Lung; Lung Lavage Fluid; Lung diseases; Marrow; Measures; Mediating; Morbidity - disease rate; Murine hepatitis virus; Mus; Myeloid Cells; Neuraminidase inhibitor; Patients; Pharmaceutical Preparations; Play; Pneumonia; Production; Proteins; Pulmonary Pathology; Recruitment Activity; Reporting; Resistance; Respiratory physiology; Role; Secondary to; Serum; Signal Transduction; Source; Testing; Therapeutic; Therapeutic Uses; Tissues; United States; Upper respiratory tract; Vascular Permeabilities; Viral; Virulent; Virus; Virus Diseases; base; cell type; chemokine receptor; cytokine; immunopathology; improved; influenzavirus; killings; lung development; macrophage; monocyte; mortality; neutrophil; pandemic disease; prevent; research study; seasonal influenza; therapy design

Mortality after infection with highly pathogenic influenza viruses, including avian H5N1 virus and the 1918 H1N1 virus, is associated with the propensity of these viruses to induce severe cytokine-mediated immunepathology, characterized by hypoxemia and hemorrhagic inflammatory edema in the lung. In addition, acute pro-inflammatory cytokine production has been correlated with the onset of fatal influenza-associated encephalopathy in children infected with influenza A viruses. Antiviral neuraminidase inhibitors are able to control viral infection if given early to patients, but no drugs have been reported to be effective in treating the cytokine-mediated lung damage. Importantly, the exact source of pathogenic cytokines during influenza infection has been not identified. However, accumulation of monocyte-derived cells in the lungs is associated with the development of lung damage in several inflammatory pulmonary diseases, and these cells have been suggested the major source of inflammatory cytokines after influenza infection. Mechanisms orchestrating the recruitment, differentiation and activation of inflammatory myeloid cells to the lung following flu infection remain elusive. The chemokine receptor CCR1 is expressed by hematopoietic cells, including monocytes, macrophages and DCs, and by some non-bone marrow-derived cells. Our preliminary data demonstrate that CCR1 deletion protects from lethal influenza infection associated immunopathology and mortality. Based on our preliminary results, we hypothesize that CCR1 deficiency prevents influenza-associated mortality by preventing activation of monocyte-derived inflammatory cells within the infected lungs. In this proposal, we will determine how CCR1 deficiency promotes protection from the immunopathology associated with pathogenic influenza infections (Aim 1) and will evaluate the potential therapeutic uses of CCR1 antagonists in treating influenza-associated immunopathology (Aim 2).

感染高致病性流感病毒（包括禽 H5N1 病毒和 1918 H1N1 病毒）后的死亡率与这些病毒诱发严重细胞因子介导的免疫病理学的倾向有关，其特征是肺部低氧血症和出血性炎症水肿。此外，急性促炎细胞因子的产生与感染甲型流感病毒的儿童致命性流感相关脑病的发病有关。抗病毒神经氨酸酶抑制剂能够 如果及早给予患者，可以控制病毒感染，但目前尚无药物可有效治疗细胞因子介导的肺损伤。重要的是，流感感染期间致病细胞因子的确切来源尚未确定。然而，单核细胞来源的细胞在肺部的积累与几种炎症性肺部疾病的肺损伤的发展有关，并且这些细胞已被研究 提示流感感染后炎症细胞因子的主要来源。流感感染后协调肺部炎症骨髓细胞的招募、分化和激活的机制仍然难以捉摸。趋化因子受体 CCR1 由造血细胞（包括单核细胞、巨噬细胞和 DC）以及一些非骨髓来源的细胞表达。我们的初步数据表明，CCR1 缺失可以防止致命性流感感染相关的免疫病理学和死亡率。基于 根据我们的初步结果，我们假设 CCR1 缺陷通过阻止受感染肺部内单核细胞衍生的炎症细胞的激活来预防流感相关的死亡。在本提案中，我们将确定 CCR1 缺陷如何促进对与致病性流感感染相关的免疫病理学的保护（目标 1），并将评估 CCR1 拮抗剂在治疗流感相关免疫病理学中的潜在治疗用途（目标 2）。